Differentiation of bone marrow derived precursors into mature T cells takes place in the thymus. During differentiation, T cells develop the receptor repertoire which allows them to recognize antigen in the context of self major histocompatibility complex (MHC) molecules. Mature T helper cells (mostly CD4+CD8-) recognize antigen in the context of class II MHC molecules, whereas cytotoxic T cells (mostly CD4-CD8+) recognize antigen in the context of class I MHC determinants. Thymic MHc-encoded determinants greatly influence the selection of the T-cell receptor repertoire. In addition to positive selection, a negative selection to eliminate self-reactive T-cell clones is thought to occur in the thymus, but how this "education" occurs is not well understood. It has been suggested that during differentiation an interaction between the T-cell receptor (TCR) and MHC-encoded determinants occurs, leading to the selection of an MHC-restricted receptor repertoire. In support of this hypothesis, class-II-specific, CD4+CD8- helper T cells fail to develop in mice neonatally treated with anti-class II monoclonal antibody (our earlier work). Our current work addresses whether the same rules apply to development of CD4-CD8+ T cells. Furthermore, the possibility that the selection of the T cell repertoire is influenced by interactions other than those between TCR's and MHC, by analyzing the role of the CD4 and CD8 molecules in development. Recent results demonstrate that, indeed, also CD4-CD8+ T cells require MHC expression for their development to occur. The significance of this project lies in: (1) understanding the factors that control development of T cells; and (2) applying this knowledge to studies on tolerance induction, which is greatly influenced by CD4- expression.